2022 Vol. 13, No. 1

In the cover paper, Yang et al. investigate the expression of PINK1 in mouse, monkey, and human tissues and found that PINK1 kinase form is more abundant in the primate brains but undetectable in the mouse tissues. Moreover, PINK1 is not enriched in mitochondria in the primate brains. Consistently, depletion of PINK1 causes neuronal loss in the monkey brain without impacting mitochondrial protein expression and morphology. Further, loss of PINK1 reduces protein phosphorylation that is important for neuronal survival. The findings suggest that the impairment of PINK1 kinase but not mitophagy accounts for the selective neurodegeneration in the PINK1 deficient monkey model.

A tribute to Professor Yong Zhao
Zheng Tan, Jun Tang, Feng Wang, Xiaocui Li, Yanlian Chen, Songyang Zhou
2022, 13(1): 1-3. doi: 10.1007/s13238-021-00875-2
PINK1 mediates neuronal survival in monkey
Zhiyu Sun, Jiangyu Ye, Junying Yuan
2022, 13(1): 4-5. doi: 10.1007/s13238-021-00889-w
The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders
Kaifan Zhang, Yan Wang, Tianda Fan, Cheng Zeng, Zhong Sheng Sun
2022, 13(1): 6-25. doi: 10.1007/s13238-020-00812-9
The serine/threonine p21-activated kinases (PAKs), as main effectors of the Rho GTPases Cdc42 and Rac, represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity. PAKs show wide expression in the brain, but they differ in specific cell types, brain regions, and developmental stages. PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines. PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders. Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment, comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases, which may also represent potential therapeutic targets of these diseases.
Research Articles
PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis
Weili Yang, Xiangyu Guo, Zhuchi Tu, Xiusheng Chen, Rui Han, Yanting Liu, Sen Yan, Qi Wang, Zhifu Wang, Xianxian Zhao, Yunpeng Zhang, Xin Xiong, Huiming Yang, Peng Yin, Huida Wan, Xingxing Chen, Jifeng Guo, Xiao-Xin Yan, Lujian Liao, Shihua Li, Xiao-Jiang Li
2022, 13(1): 26-46. doi: 10.1007/s13238-021-00888-x
In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.
cGAS guards against chromosome endto-end fusions during mitosis and facilitates replicative senescence
Xiaocui Li, Xiaojuan Li, Chen Xie, Sihui Cai, Mengqiu Li, Heping Jin, Shu Wu, Jun Cui, Haiying Liu, Yong Zhao
2022, 13(1): 47-64. doi: 10.1007/s13238-021-00879-y
As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.
Isogenic human pluripotent stem cell disease models reveal ABRA deficiency underlies cTnT mutation-induced familial dilated cardiomyopathy
Bin Li, Yongkun Zhan, Qianqian Liang, Chen Xu, Xinyan Zhou, Huanhuan Cai, Yufan Zheng, Yifan Guo, Lei Wang, Wenqing Qiu, Baiping Cui, Chao Lu, Ruizhe Qian, Ping Zhou, Haiyan Chen, Yun Liu, Sifeng Chen, Xiaobo Li, Ning Sun
2022, 13(1): 65-71. doi: 10.1007/s13238-021-00843-w
Persisting lung pathogenesis and minimum residual virus in hamster after acute COVID-19
Lunzhi Yuan, Huachen Zhu, Ming Zhou, Jian Ma, Rirong Chen, Liuqin Yu, Wenjia Chen, Wenshan Hong, Jia Wang, Yao Chen, Kun Wu, Wangheng Hou, Yali Zhang, Shengxiang Ge, Yixin Chen, Quan Yuan, Qiyi Tang, Tong Cheng, Yi Guan, Ningshao Xia
2022, 13(1): 72-77. doi: 10.1007/s13238-021-00874-3